Dr. Bailey-Wilson has been working for over 30 years to detect genetic risk factors for lung cancer and possible gene-gene and/or gene-environment interactions. The purpose of her study of lung cancer is to identify a gene or genes that contribute to lung cancer susceptibility. In this fiscal year, family data have been collected in Louisiana. Data collection is expected to continue for several more years. Dr. Bailey-Wilson is a founder of the Genetic Epidemiology of Lung Cancer Consortium (GELCC) for the purpose of obtaining additional family data from a large group of collaborative investigators. The first genome-wide significant linkage of a lung cancer susceptibility locus on chromosome 6q was published by us. A paper characterizing the linkage evidence after using ordered subset analysis was also published by us using smoking and other linkage regions as the ordering variable. This work suggested that several additional variants may increase risk for lung cancer in these highly aggregated families. We have previously published evidence that RGS17 is a tumor suppressor gene that is associated with LC risk; it may be involved in explaining part but not all of the 6q linkage signal. Additional sequencing studies of the region are underway along with studies of a knock-out mouse model (in the lab of collaborator Ming You). A new set of families was recently genotyped for a SNP marker linkage panel and data are being analyzed. A large GWAS on familial cases vs elderly, smoking controls was genotyped at the Center for Inherited Disease Research and a manuscript is in preparation. We are analyzing targeted sequence data in the 6q region in our most strongly linked families and analyses are ongoing. We have performed whole exome sequencing in collaboration with Dr. Margaret Spitz of Baylor University on 60 of our family-history-positive patients and analyses are ongoing. A new paper suggesting an additional candidate locus (PARK2) for LC susceptibility in a small number of families and based on all sequence data available to date was published this year (1). We continue to sequence additional families. Whole exome sequencing studies on about 100 affected relatives in our highly aggregated families has started in collaboration with Dr. Ramaswamy Govindan, Washington University. We are currently analyzing the first 5 of these families and expect to receive the remaining data in the next year. Another major aim of Dr. Bailey-Wilson's research is to determine genetic risk factors in families with human prostate cancer. Papers published previously by our large group of collaborators have shown evidence of PRCA susceptibility genes in regions of chromosomes 1 (HPC1), 3p, 11q, 8 and Xq (HPCX). These results have been followed up by intensive linkage analyses of additional families to markers in these regions and in other regions that showed some mild evidence of linkage in the initial genome scans. Previously, our group identified mutations in the ribonuclease-L (RNASEL) gene as being the locus in our chromosome 1 linkage region (HPC1) causing increased risk to prostate cancer and showed evidence that mutations in the MSR1 gene on chromosome 8 plays a role in prostate cancer risk. In collaboration with Dr. Johanna Schleutker's group, we published new linkage analyses confirming linkage on chromosome 17 in a set of highly aggregated Finnish prostate cancer families. Some of our collaborators in the International Consortium for Prostate Cancer Genetics showed that HOXB13 is a good candidate for this locus and, follow-up in Finland and in the ICPCG families support this as a causal locus. Dr. Bailey-Wilson's group is analyzing fine-mapping and sequence data in the African-American Hereditary Prostate Cancer (AAHPC) families. We work with the International Prostate Cancer Genetics Consortium (ICPCG) to try to localize prostate cancer loci more rapidly. We are also collaborating with Dr. Diptasri Mandal on linkage studies of prostate cancer in African-American men from Louisiana. In addition to the ongoing linkage studies, the ICPCG is performing whole exome sequencing studies in our highly-aggregated prostate cancer families and we are starting to analyze these data in the AAHPC families and are leading the ICPCG analyses of AA families. We are currently working closely with several groups in the ICPCG on a project to predict the effects of genetic mutations on proteins. This work will be used to interpret the sequence data that we are currently analyzing for the ICPCG. As an adjunct to the family-based studies of prostate cancer described above, Dr. Bailey-Wilson is collaborating with Drs. Trent and Carpten of Translational Genomics, Dr. Barbara Nemesure of State University of New York at Stony Brook and Drs. Anselm Hennis and Lyndon Waterman of the University of the West Indies, in Barbados, on a study of the genetic epidemiology of prostate cancer and breast cancer in Barbados. These cancers occur at very high rates in the Barbadian population. Data collection is now complete for this large prostate case-control study, with a sample of about 1000 each. Several papers on breast and prostate cancer risk factors in this population have been published. This year, we have published results of our analyses of fine-mapping SNPs on chromosome 8 to follow-up previous reports of linkage and association to prostate cancer in this region in other studies (2). We are analyzing genome-wide association data on a subset of the study participants. We plan to analyze these data accounting for local admixture and plan to expand to a GWAS of the entire dataset in the future. Dr. Bailey-Wilson is working on a collaborative study of Carcinoid tumor with Drs. Steven Wank of NIDDK and Drs. Alejandro Schaffer and Richa Agarwala of CIT/NIH. In this study of this rare familial tumor, we are comparing linkage results in several large, highly aggregated families with whole-exome sequence data to attempt to localize genes responsible for this highly-penetrant familial tumor. In one of these families, our linkage analyses were used to localize a causal variant shared by all affecteds and cosegregating with disease in the large family. Dr. Wanks group has characterized this variant and shown that it is causal, and a paper presenting these results was published this year (3). We are now proceeding with additional linkage and sequence analysis of additional carcinoid tumor families. Dr. Bashira Charles, a Research Fellow, is developing a collaborative DNA sequencing study of Burketts Lymphoma (independent of Dr. Bailey-Wilson) in a sample of Children from Uganda. Study design and planning are ongoing.